HU180091B - Process for producing sodium salt of 6-square bracket-d-bracket-minus-aracket closed-alpha-aracket-4-hydroxy-1,5-naphtiridine-3-carboxamido-bracket closed-phenylacetamido- or -p-hydroxy-phenylacetamido-square bracket closed-pename-3-carboxylic acids - Google Patents

Abstract

PURPOSE:To obtain the title compound in high purity readily, by converting an antibacterial crude sodium salt of 6-acylaminoacylamidopenicillanic acid into a novel DMSO adduct which is crystalline and has improved storage stability, and by removing the DMSO. CONSTITUTION:Crude sodium salt of 6-[D--alpha-(4-hydroxy-1, 5-naphthyridine- 3-carboxamido)-(rho-hydroxy or unsubstituted)-phenylacetamido]-penicillanic acid is reacted with DMSO to form its DMSO adduct as crystals. DMSO is then removed from the adduct by adding a solvent, e.g. acetone, which will not dissolve the objective substance, to an aqueous solution of the adduct, whose pH is adjusted, to take out the substance as crystals. EFFECT:Wide antibacterial spectrum and particularly effective for bacillus pyocyaneus.

Description

Japan

Representative: No. 14 of the Bp. ÜMK, Budapest

A method of 6- [D (-) - <X (4-hydroxy-l ₉ 5-naphthyridine-3-carboxamido) -fenilacetamido- or p-hydroxytridec-phenylacetamido] penem-3-karboüsav-purifying nátriunisó

2

The present invention relates to a novel process for the purification of penam-3-carboxylic acid derivatives of formula (I) wherein R is hydrogen or hydroxy. Thus, according to the present invention, the sodium salt of 6- [D (-) -? - (4-hydroxy-1,5-naphthyridine-3-carboxamido) phenylacetamido] penam-3-carboxylic acid and 6- [D (-) - The sodium salt of? - (4-hydroxyl, 5-naphthyridine-3-carboxamido) -? - hydroxyphenylacetamido] -penam-3-carboxylic acid is prepared in pure form.

It is known that 6- [D (-) -? - (4-hydroxy-1,5-naphthyridine-3-carboxamido) phenylacetamido] -penam-3-carboxylic acid (hereinafter "Compound A") and

6- [D (-) -? - (4-Hydroxy-1,5-naphthyridine-3-carboxamido) -p-hydroxyphenylacetamido] -penam-3-carboxylic acid (hereinafter "Compound B"), and the non-toxic salts of these compounds have very strong antimicrobial activity against Pseudomonas aeruginosa and have a much broader antimicrobial spectrum than ampicillin, amoxicillin, carbenicillin, sulbenicillin and similar penam-3-carboxylic acids (17994/1975, Japanese Patent Publication No. 82683/1974).

The sodium salt of Compound A or Compound B is prepared by coupling ampicillin or amoxicillin with 4-hydroxy-1,5-naphthyridine-3-carboxylic acid according to known procedures. The coupling reaction is carried out by known methods widely used in peptide chemistry, such as the mixed anhydride method, the acid chloride method, the activated ester method or the dicyclohexylcarbodiimide activation method. However, under known reaction conditions, significant amounts (about 3 to 10% by weight) of by-products are formed by cleavage of the? -Lactam ring. If the purified product is stored at room temperature for an extended period of time, the product will accumulate an increasing amount of contaminating by-products formed by the cleavage of the? -Lactam ring. A further disadvantage is that when 6-aminopenicillanic acid is mixed with α- (4-hydroxy-1,5-naphthyridine-3-carboxamido) phenylacetic acid or α- (4-hydroxy-1,5-naphthyridine-3) according to the methods used in peptide chemistry. -carboxamido) -p-hydroxyphenylacetic acid, the compound "A" and the compound "B" are formed in the state contaminated with the L-isomer.

Contaminants and L-isomers formed by cleavage of the?-Lactam ring can only be removed from the final product by very complex purification operations. A further difficulty arises from the fact that during purification operations commonly used in organic chemistry, the unstable β-lactam ring may be ruptured, thus further increasing the amount of contaminating degradation products.

In our experiments we found that a

-1180,091 /? - lactam ring rupture during purification, and thus enrichment of impure degradation products, can be completely eliminated by purifying the sodium salt of Compound A or Compound B via the addition of dimethyl sulfoxide. Compound A and the sodium salt of Compound B form an adduct which crystallizes readily with dimethylsulfoxide, but the impurity degradation products do not form an adduct with this reagent. The resulting dimethylsulfoxide adduct is readily cleaved by aqueous media and liberates pure Compound A sodium salt and Compound B sodium salt. A further advantage of dimethylsulfoxide adducts is that they are extremely stable compounds and can be stored for very long periods without risk of degradation.

Accordingly, the present invention relates to a process for preparing pure 6- [D (-) - N - (4-hydroxy-1,5-naphthyridine-3-carboxamido) phenylacetamido] pentane-3-carboxylic acid sodium salt and pure 6- [D - (-) -? - (4-Hydroxy-1,5-naphthyridine-5-carboxamido) -? - hydroxyphenylacetarnido] -penam-3-carboxylic acid sodium salt. an adduct of formula (II) with the sodium salt of dimethyl sulfoxide, wherein R is as defined above, is treated with a water-containing liquid medium and the pure compound of formula (I) is isolated from the resulting mixture. in which the sodium salt of Compound A or Compound B is poorly soluble, during which the Compound A or Compound B sodium salt is precipitated from the reaction mixture in a crystalline form. sodium salt of compound as well as the sodium salt of Compound B in an extremely pure state.

Preferably, the process of the present invention is based on the dimethylsulfoxide adduct formed from the contaminated sodium salt of Compound A and Compound B. Although the preparation of dimethylsulfoxide adducts is not within the scope of the present invention, for the sake of clarity the preparation of dimethylsulfoxide adducts of formula (II) is described in detail below.

The dimethylsulfoxide adducts can be prepared by reaction of the corresponding compound of formula (I) with dimethylsulfoxide. For example, the contaminated sodium salt of Compound A or Compound B can be dissolved or contacted with dimethyl sulfoxide and the crystalline adduct precipitated is isolated from the reaction mixture in a known manner. The adducts of formula (II) are obtained in an extremely pure state.

As the liquid medium containing dimethyl sulfoxide, pure dimethyl sulfoxide or mixtures of dimethyl sulfoxide with organic solvents such as alcohols (such as methanol, ethanol or isopropanol), acetonitrile, acetone or hydrocarbons (such as benzene, toluene or hexane) may be used. Water may also be added to the liquid medium containing dimethyl sulfoxide. Mixtures of dimethylsulfoxide with alcohols are particularly preferred.

The reaction temperature is not critical to the formation of the dimethylsulfoxide adducts; however, the reaction is preferably carried out at room temperature (5 to 20 ° C) to about 60 ° C. If the reaction is carried out at temperatures above 60 ° C, the sodium salt of Compound A and the sodium salt of Compound B may be degraded, resulting in a decrease in the yield of the adduct with dimethylsulfoxide; while at temperatures below room temperature the dimethylsulfoxide adduct is difficult to form. The reaction is usually complete within 24 hours; it usually takes 1-2 hours to form the adduct.

The purification sodium compound of Compound A or Compound B may also be formulated in the liquid medium containing dimethyl sulfoxide itself. For example, Compound A or Compound B, or their ammonium or amine salts, can be reacted with sodium or a sodium compound in a liquid medium containing dimethyl sulfoxide. During the reaction, the adduct of compound A or the sodium salt of compound B with dimethylsulfoxide is precipitated as crystals. Exemplary amine salts include the salts with triethylamine, tri-n-butylamine, dibenzylamine, N-benzyl-N'-phenethylamine, 1-ephenamine, N, N-dibenzylethylenediamine, procaine, dehydroabiethyl ethylenediamine and arginine. Examples of sodium compounds include sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium acetate, sodium 2-ethylhexanoate, sodium methoxide, sodium ethoxide, sodium phenoxide, sodium thiocyanate and acetone acetate. Sodium salts of organic carboxylic acids such as 2-ethylhexanecarboxylic acid are particularly preferred.

In some cases, the solution of the dimethylsulfoxide adduct may be adjusted to a suitable pH before the adduct is degraded. Usually the sodium compounds listed above are used to adjust the pH.

Aqueous aqueous media can be used to decompose the dimethylsulfoxide adducts of formula (II) using a mixture of water and one or more polar organic solvents such as alcohol (such as methanol, ethanol or isopropanol), dioxane, tetrahydrofuran, dimethylformamide, acetonitrile or acetone. Aqueous alcohols such as aqueous methanol are particularly preferred. Although the water content of the liquid medium is not a decisive factor, generally more favorable results are obtained when using relatively low water content media.

The decomposition temperature of the dimethyl sulfoxide adducts is not critical. The reaction is usually carried out at room temperature (5-20 ° C) or less. The reaction usually takes from 20 to 60 minutes, usually about 30 minutes, from the dissolution of the dimethylsulfo-2180,091 xid adduct.

For example, acetonitrile, isopropanol, ether, isopropyl ether, tetrahydrofuran, dichloromethane and the like can be used as the solvent to precipitate the liberated sodium salts.

The following examples illustrate the invention without limiting it. In Example A, a known preparation of the sodium salt of the impure 6- [D (-) -? - (4-hydroxy-1,5-naphthyridine-3-carboxamido) phenylacetamido] penam-3-carboxylic acid is disclosed. In the following examples, the preparation of the starting materials of formula (II) and their degradation are described first. The purity values (% by weight) in the Examples were determined by high performance liquid chromatography, which provides very accurate and reliable results when tested for penicillin compounds [K. Tsuji et al., J. Pharm. Sci. 64, 1543 (1975); I. Umeda et al., J. Pharm. Soc. Japan 99, 765 (1979)]. In our experience, the degree of purity of the penam-3-carboxylic acid derivatives of formula (I) cannot be characterized with sufficient accuracy by the physical constants of the products; For example, the crude sodium salt of 6- [D (-) -? - (4-hydroxy-1,5-naphthyridine-3-carboxamido) phenylacetamido] pentan-3-carboxylic acid, with a purity of 92.0%, m.p. 265 ° C. while the product of 99.2% purity has a melting point of 265-270 ° C. The purity of the product thus obtained cannot be adequately deduced from the melting point or decomposition point.

Liquid chromatography was performed on a Du Pont 830 2.1 mm diameter, 1 cm long Zipax SAX column at 56 atmospheres pressure, 40 ° C, and 16 times the sensitivity. To prepare the sample, 10 mg of the test substance was dissolved in 1 mL of water and 1.5 of the resulting solution was used for the assay. The carrier medium was prepared as follows: To 200 ml of 0.05 M aqueous sodium hydroxide solution was added 0.005 mol of citric acid and the solution was diluted to 1 liter with water. Sodium nitrate (0.015 mol) was added to 950 ml of the resulting solution and the pH of the mixture was adjusted to 5.3 with approximately 50 ml of 0.005 molar aqueous sodium hydroxide solution.

for purposes of comparison, it is reported that the crude 6- [D (-) -? - (4-hydroxy-1,5-naphthyridine-3-carboxamido) phenylacetamido] pentam-3-carboxylic acid sodium salt of crude 6- [D (-) -? The crude product is dissolved in 5 parts by weight of aqueous methanol, the insoluble material is filtered off and the crystalline product is precipitated from the filtrate with acetone. According to high performance liquid chromatography, 90% pure product was obtained from this starting material with a purity of 92.0%; thus, the crude product cannot be purified by this process.

Example A

Step 1: Preparation of N- (4-hydroxy-1,5-naphthyridine-3-carbonyloxy) succinimide

To a mixture of 47.5 kg of dimethylformamide and 4.7 kg of pridine are added 2.8 kg of 4-hydroxy-1,5-naphthyridine-3-carboxylic acid and 2.2 kb of N-hydroxysuccinimide. 2.1 kg of thionyl chloride were added dropwise to the reaction mixture while stirring at room temperature, and the mixture was stirred at room temperature for 5 hours. The precipitated crystals are filtered off, washed with acetone and dried under reduced pressure.

4.3 kg of 97% pure N- (4-hydroxy-1,5-naphthyridine-3-carbonyloxy) succinimide are obtained.

Step 2: Preparation of the sodium salt of 6- [D (-) -? - (4-hydroxy-1,5-naphthyridine-3-carboxamido) phenylacetamido] pentane-3-carboxylic acid

To a solution of 2.5 kg of triethylamine in 18.0 kg of dimethyl sulfoxide was added 5.0 kg of ampicillin trihydrate and 3.45 kg of N- (4-hydroxy-1,5-naphthyridine-3-carbonyloxy) succinimide. The reaction mixture was stirred at room temperature and then 64 kg of acetone was poured into the mixture. The precipitated white crystalline material is filtered off, washed with acetone and finally dried under reduced pressure. 6- [D (-) -? - (4'-Hydroxy-1,5-naphthyridine-3-carboxamido) -phenylacetamido] -penam-3-carboxylic acid triethylamine salt is obtained.

The resulting triethylamine salt was dissolved in 2.4 kg of methanol containing 7.8 kg of dimethyl sulfoxide and 2-ethylhexanecarboxylic acid sodium salt at room temperature with stirring for 30 minutes. The reaction mixture was then charged with 94 kg of acetone. The precipitated white crystalline product was filtered off and washed with acetone. The resulting wet filter cake was dissolved in methanol (16 kg), the insoluble material was filtered through celite and acetone (94 kg) was added to the filtrate. The precipitated white crystalline material was filtered off, washed with acetone and finally dried under reduced pressure. 5.3 kg of sodium salt of 6- [D (-) -? - (4-hydroxy-1,5-naphthyridine-3-carboxamido) -phenylacetamido] -penam-3-carboxylic acid with 95.5% purity are obtained.

Example 1

5.0 kg of crude sodium salt of 6- [D (-) c- (4-hydroxy-1,5-naphthyridine-3-carboxamido) -phenylacetamido] -penam-3-carboxylic acid at 95.5% purity at room temperature 10 , 1 kg of dimethylsulfoxide and

Dissolve in 6.2 kg of methanol. The reaction mixture was then heated to 50-55 ° C and stirred at this temperature for 1 hour. The precipitated white crystal, 5θ, was filtered off, washed with 1.0 kg of dimethyl sulfoxide and 0.6 kg of methanol, then with 16 kg of acetone and finally dried. 4.2 kg of the sodium salt of dimethylsulfoxide 6- [D (-) -? - (4-hydroxy-1,5-naphthyridine-3-carboxamido) phenylacetamido] pentane-3-carboxylic acid are obtained; purity: 99.5%.

of the dimethylsulfoxide adduct obtained above was dissolved in 10.8 kg of 93% aqueous methanol and 84 kg of ace60 tons were added dropwise to the methanolic solution. The precipitated white crystalline material was filtered off, washed with 14 kg of acetone and dried. 3.5 kg of sodium salt of 6- [D (-) - α- (4-hydroxy-1,5-naphthyridine-3-carboxamido) phenylacetamido] pentane-3-carboxylic acid (99.2% purity) 65 are obtained.

-3180,091

Example 2

6.4 kg of crude sodium salt of 6- [D (-) - a (4-hydroxy-1,5-naphthyridine-3-carboxamido) phenylacetamido] pentane-3-carboxylic acid, 92.0% purity, containing the impurity formed by the cleavage of the? -lactam ring, dissolved in a mixture of 13 kg of dimethyl sulfoxide and 8 kg of methanol. The reaction mixture was heated to 50-55 ° C and stirred at this temperature for 1 hour. The precipitated white crystalline product was filtered off and washed with a mixture of 1.3 kg of dimethyl sulfoxide and 0.8 kg of methanol followed by 20 kg of acetone.

5.3 kg of 99.3% purity of 6- [D (-) -? - (4-hydroxyl, 5-naphthyridine-3-carboxamido) -phenylacetamido] penam-3-carboxylic acid sodium salt dimethylsulfoxide adduct; mp 265-270 ° C (dec).

Analysis calculated for C ₂ ; H _{2> 5} H ₇ NS ₂ Na:

Found: C, 52.2; H, 4.5; N, 11.3; S, 10.3; C: 52.0%, H: 4.5%, N: 11.2%, S: 10.5%.

of the dimethylsulfoxide adduct prepared above was dissolved in 13.5 kg of 93% aqueous methanol and 105 kg of acetone was added dropwise. The precipitated white crystalline material is filtered off, washed with 17 kg of acetone and finally dried. 4.3 kg of sodium salt of 6- [D (-) -? - (4-hydroxy-1,5-naphthyridine-3-carboxamido) phenylacetamido] pentane-3-carboxylic acid with a purity of 99.0% are obtained.

Example 3

7.1 kg of triethylamine of 6- [D (-) -? - (4-hydroxy-1,5-naphthyridine-3-carboxamido) phenylacetamido] pentane-3-carboxylic acid (purity: 98.5%), 13 kg of dimethylsulfoxide, Dissolve in a mixture of 2 kg of 2-ethylhexanecarboxylic acid sodium salt and 8 kg of methanol. The solution was heated to 50-55 ° C and stirred at this temperature for 1 hour. The precipitated white crystalline product was filtered off, washed with a mixture of 1.3 kg of dimethyl sulfoxide and 0.8 kg of methanol, then with 20 kg of acetone and finally dried. 5.2 kg of a sodium salt dimethylsulfoxide adduct of 6- [D (- (a) 4-hydroxy-1,5-naphthyridine-3-carboxamido) -phenylacetamidojpenam-3-carboxylic acid with a purity of 99.1% is obtained.

of the dimethylsulfoxide adduct obtained above were dissolved in 13.5 kg of 93% aqueous methanol and 105 kg of acetone were added dropwise. The precipitated white crystalline material is filtered off, washed with 17 kg of acetone and dried. 4.2 kg of 98.8% pure sodium salt of 6- [D (-) -? - (4-hydroxy-1,5-naphthyridine-3-carboxamido) phenylacetamido] pentane-3-carboxylic acid are obtained.

Example 4

6.4 kg of crude sodium salt of 6- [D (-) -? - (4-hydroxy-1,5-naphthyridine-3-carboxamido) phenylacetamido] pentan-3-carboxylic acid containing 0.2% of the L-isomer. Phenylglycine is dissolved in a mixture of 13 kg of dimethyl sulfoxide and 8 kg of methanol at room temperature. The resulting solution was heated to 50-55 ° C and stirred at this temperature for 1 hour. The precipitated white crystalline product was filtered off, washed with a mixture of 1.3 kg of dimethylsulfoxide and 0.8 kg of carboxamido) phenylacetamido-penam-3-methanol, followed by 20 kg of acetone and dried. 5.2 kg of the 6- [D (-) -? - (4-hydroxy-1,5-naphthyridine-3-carboxamido) phenylacetamido] penam-3-carboxylic acid sodium salt dimethyl sulfoxide adduct are obtained.

of the dimethylsulfoxide adduct obtained above were dissolved in 13.5 kg of 93% aqueous methanol and 105 kg of acetone were added dropwise. The precipitated white crystalline material is filtered off, washed with a mixture of 1.3 kg of dimethyl sulfoxide and 0.8 kg of methanol, then with 20 kg of acetone and finally dried. 4.2 kg of sodium salt of 6- [D (-) -? - (4-hydroxy-1,5-naphthyridine-3-carboxamido) phenylacetamido] pentane-3-carboxylic acid are obtained, which is less than 0.05% by weight. Contains L-isomer.

Example 5

6.4 kg of sodium salt of 6- [D, La- (4-hydroxy-1,5-naphthyridine-320-carboxamido) -phenylacetamidopen-3-carboxylic acid containing 49.5% of the L-isomer at room temperature, 13 kg of dimethylsulfoxide and 8 kg of methanol. The mixture was heated to 50-55 ° C and stirred at this temperature for 1 hour. The precipitated white crystalline material was filtered off, washed with a mixture of 1.3 kg of dimethyl sulfoxide and 0.8 kg of methanol, then with 20 kg of acetone and finally dried. 2.1 kg of 6- [D (-) - <c- (4-hydroxy-1,5-naphthyridine-3-carboxamide) phenylacetamido] penam-3-carboxylic acid sodium salt dimethyl sulfoxide adduct are obtained, containing 0.1% of the L-isomer.

Dissolve 5 kg of the dimethylsulfoxide adduct prepared above in 5.5 kg of 93% aqueous methanol 35 and add 50 kg of acetone dropwise. The precipitated white crystalline material is filtered off, washed with 8 kg of acetone and dried. 1.7 kg of the sodium salt of 6- [D (-) -? - (4-hydroxy-1,5-naphthyridine-3-carboxamido) -phenylacetamido] -penam-3-carbonyl-40- (0.1%) L- contains isomer.

Example 6

14.3 kg of crude 6- [D (-) 45c- (4-hydroxy-1,5-naphthyridine-3-carboxamido) -hydroxyphenylacetamido] -penam-3-carboxylic acid sodium salt, 96.0% containing the impurity decomposition product of the? -lactam ring, dissolved at room temperature in a mixture of 27 kg of dimethyl sulfoxide and 16.5 kg of methanol and stirred for 1 hour at room temperature. The precipitated white crystalline material was filtered off, washed with a mixture of 2.7 kg of dimethyl sulfoxide and 1.7 kg of methanol, then with 40 kg of acetone, and finally dried. 8.0 kg of 99.6% pure 6- [D (-) -? - (4-hydroxy-1,5-naphthyridine-3-carboxamido) -? - hydroxyphenylacetamido] -penam-3-carboxylic acid; yielding the sodium salt dimethylsulfoxide adduct; mp 275-280 ° C (dec).

Analysis for C 7 H ₂ O ₂ and Na ₂ S ₅ N ₈ O: Calculated: C 50.9%, H 4.4%, N 11.0%, S, 10.1%; Found: C, 51.0; H, 4.4; N, 11.2; S, 10.3.

kg of dimethyl sulfoxide adduct prepared as described above was dissolved in 22 kg of 93% aqueous methanol-4180 091 and 170 kg of acetone was added dropwise. The precipitated white crystalline product is filtered off, washed with 27 kg of acetone and dried.

7.5 kg of sodium salt of 6- [D (-) -? - (4-hydroxy-1,5-naphthyridine-3-carboxamido) -p-hydroxyphenylacetamido] pentane-3-carboxylic acid, having a purity of 98.8% we get.

Example 7

15.1 kg of 98.4% pure 6- [D (-) -? - (4-Hydroxy-1,5-n-thyridine-3-carboxamido) -p-hydroxyphenylacetamido] -penam-3- Triethylamine carboxylic acid was dissolved in a mixture of 27 kg of dimethyl sulfoxide, 4 kg of 2-ethylhexanecarboxylic acid sodium salt and 16.5 kg of methanol and the resulting mixture was stirred for 1 hour at room temperature. The precipitated white crystalline material was filtered off, washed with a mixture of 2.7 kg of dimethylsulfoxide and 1.7 kg of methanol, followed by 40 kg of acetone and finally dried. 7.8 kg of 99.5% pure 6- [D (-) -? - (4-hydroxy-1,5-naphthyridine-3-carboxamido) -? - hydroxyphenylacetamido] -penam-3-carboxylic acid; yielding the sodium salt dimethyl sufoxide adduct.

7.5 kg of the dimethylsulfoxide adduct prepared above are dissolved in 20 kg of 93% aqueous methanol and 160 kg of acetone are added dropwise. The precipitated white crystalline product was filtered off, washed with 25 kg of acetone and dried. 7 kg of 98.6% pure sodium salt of 6- [D (-) -? - (4-hydroxy-1,5-naphthyridine-3-carboxamido) -p-hydroxyphenylacetamido] pentane-3-carboxylic acid are obtained. .

Example 8

6.5 kg of sodium salt of 6- [D, Lα- (4-hydroxy-1,5-naphthyridine-3-carboxamido) -p-hydroxyphenylacetamido] pentane-3-carboxylic acid containing 50.1% of the lysomer at room temperature 13 Dissolve 1 kg of dimethyl sulfoxide in 8 kg of methanol and stir at room temperature for 1 hour. The precipitated white crystalline product was filtered off, washed with a mixture of 1.3 kg of dimethyl sulfoxide and 0.8 kg of methanol, then with 20 kg of acetone and finally dried. 1.8 kg of the sodium salt of dimethyl sulfoxide of 6- [D (-) -? - (4-hydroxy-1,5-naphthyridine-3-carboxamido) -p-hydroxyphenylacetamido] -penam-3-carboxylic acid is obtained, Contains 1% L-isomer.

1.8 kg of the dimethylsulfoxide adduct obtained above are dissolved in 5 kg of 93% aqueous methanol and 50 kg of acetone are added dropwise. The precipitated white crystalline material is filtered off, washed with 8 kg of acetone and dried. 1.4 kg of the sodium salt of 6- [D (-) -? - (4-hydroxy-1,5-naphthyridine-3-carboxamido) -p-hydroxyphenylacetamido] pentamine-3-carboxylic acid are obtained. The product is 98.6% pure and contains 0.1% L-isomer.

Claims (2)

Patent claims A process for the preparation of penam-3-carboxylic acid derivatives of formula I wherein R is hydrogen or hydroxy Sodium salt of 20 - i.e. 6- [D (-) -? - (4-hydroxy-1,5-naphthyridine-3-carboxamido) phenylacetamido] pentane-3-carboxylic acid, or 6- [D (-) - a- Purification of the sodium salt of (4-hydroxy-1,5-naphthyridine-3-carboxamido) -p-hydroxyphenylacetamido] penam-3-carboxylic acid, characterized in that the impure compounds of formula (I) are The adduct of formula (I), wherein R is as defined above, is treated with a water-containing liquid medium, then a poorly soluble liquid of the compound of formula (I) is added to the reaction mixture and the precipitated solid pure product is isolated. 2. The method of claim 1, wherein (II) Sodium salt of 6 [D (-) -? - (4-hydroxy-1,5-naphthyridine-3-carboxamido) -phenylacetamido] -penam-3-carboxylic acid and contaminated 6- [D (-) - The adduct prepared by reaction of the sodium salt of α- (4-hydroxy-1,5-naphthyridine-3-carboxamido) -p-hydroxy-4-phenylacetamido] penam-3-carboxylic acid with dimethylsulfoxide is used. Instead of the notifier, the agent shall: 1 formula page Responsible for publishing: Director of Economic and Legal Publishing 83. 30 808 Petőfi Nyomda, Kecskemét - Chief Executive Officer: István Ablaka Director -5180091 International classification: